Regioselective Green Electrochemical Approach to the Synthesis of

Sep 18, 2015 - A regioselective green synthesis of nitroacetaminophen derivatives was carried out by electrochemical oxidation of acetaminophen, N-(2-...
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Regioselective Green Electrochemical Approach to the Synthesis of Nitroacetaminophen Derivatives Eslam Salahifar,† Davood Nematollahi,*,† Mehdi Bayat,† Amir Mahyari,† and Hadi Amiri Rudbari‡ †

Faculty of Chemistry, Bu-Ali-Sina University, Hamedan 65174, Iran Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran

‡

S Supporting Information *

ABSTRACT: A regioselective green synthesis of nitroacetaminophen derivatives was carried out by electrochemical oxidation of acetaminophen, N-(2-hydroxyphenyl)acetamide, and 1-(4(4-hydroxyphenyl)piperazin-1-yl)ethanone in the presence of nitrite ion as a nucleophile. The present work has led to the development of a reagentless green and facile electrochemical method for the synthesis of some nitroacetaminophen derivatives.

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two-electron wave for the PAC/PBQ redox couple at E1/2 0.44 V (Figure 1, curve a).3 At this pH value, the peak current ratio

edical research shows that, when used in therapeutic doses, acetaminophen (PAC) is a safe drug. However, some adverse effects such as kidney and liver damage have been reported when overdosed.1 In the presence of oxidizing enzymes such as cytochrome P-450, 5−10% of acetaminophen converts to N-acetyl-p-benzoquinone-imine (PBQ). This compound is a hepatotoxic agent, and its covalent bonding to the nucleic acids and proteins is responsible for the kidney and liver damage.2 Under normal conditions, detoxification of this compound is carried out quickly by reaction with glutathione.3 In overdose, however, the amount of cellular glutathione is insufficient to detoxify PBQ, resulting in the reaction of PBQ with cellular macromolecules, hepatocellular injury, and cell death. Based on this scientific reality, we chose to synthesize a more difficult-to-oxidize acetaminophen derivative. This may lead to minimization of the side effects of acetaminophen and improve the efficacy of the therapy. In order to achieve this objective, we decided to nitrate acetaminophen. A literature survey indicated that only a few reports on the nitration of PAC have been published.4 Nevertheless, these methods have some disadvantages such as heavy metal pollution, safety problems associated with overnitration, low yield, the use of strongly acidic media, and tedious workup. These disadvantages have encouraged us to develop electrochemical nitration of organic compounds. In this work, a green electrochemical method for the nitration of PAC, N-(2-hydroxy phenyl)acetamide (OAC), and 1-(4-(4-hydroxyphenyl)piperazin-1-yl)ethanone (APIP) is reported. This method exhibits a high degree of regioselectivity toward the nitration of PAC and OAC compared with other nitration methods. In an aqueous acetate buffer solution (c = 0.2 M, pH = 5.0), the cyclic voltammogram of PAC displays a quasi-reversible © XXXX American Chemical Society

Figure 1. Cyclic voltammograms of PAC (1.0 mM): (a) in the absence, (b) in the presence of 20 mM, and (c) in the presence of 40 mM nitrite ion. (d) Cyclic voltammogram of NO2− (2.0 mM) at glassy carbon electrode, in acetate buffer solution (c = 0.2 M, pH = 5.0). Scan rate: 10 mV s−1. Temperature = 25 ± 1 °C.

(IpC1/IpA1) is near 1, which shows that PBQ is stable on the time scale of cyclic voltammetry measurements. In the presence of nitrite ion, the current of cathodic peak C1 (IpC1) decreases and a new cathodic peak (C2) appears at more negative potentials (−0.48 V vs Ag/AgCl). It was found that both IpC1/ IpA1 and IpC1/IpC2 decrease with increasing nitrite ion concentration (Figure 1) as well as decreasing potential sweep rate. The existence of a subsequent chemical reaction between PBQ and nitrite ion is supported by the following evidence:5 (a) the decrease of IpC1/IpA1, (b) the increase of IpC1/IpA1 with Received: June 25, 2015

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DOI: 10.1021/acs.orglett.5b01837 Org. Lett. XXXX, XXX, XXX−XXX

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molecule that has two different sites, I and II, leading to two different chemical reactions between PBQ and nitrite ion (Scheme 2). However, single-crystal X-ray diffraction analysis of the synthesized compound7 confirms regioselective formation of one isomer (2NPAC).

increasing scan rate, (c) the appearance of the cathodic peak C2 at more negative potentials, (d) the increase of IpC1/IpC2 with increasing scan rate, and (e) the decrease of IpC1/IpA1 and IpC1/ IpC2 with increasing nitrite ion concentration. Controlled-potential coulometry (CPC) was carried out in the same solution as used in Figure 1 containing both PAC and nitrite ion at 0.45 V versus Ag/AgCl to determine the number of transferred electrons per PAC molecule. Figure 2I displays

Scheme 2. Possible Nitration Compounds

The synthesis of 2NPAC was also performed via the constant current electrolysis under the same conditions as described for controlled-potential electrolysis. Our data show that the highest yield (84%) was obtained at a current density of 0.1 mA/cm2. In this current density, the electrode potential remained nearly constant at +0.45 V (E1/2 of PAC/PBQ redox couple is +0.44 V), which is necessary for selective oxidation of PAC (Figure 2II) (see the Supporting Information). In order to investigate the electrochemical properties of 2NPAC, cyclic voltammograms of a saturated solution of 2NPAC in aqueous acetate buffer (pH = 5.0, c = 0.2 M) were recorded (Figure 3).

Figure 2. (I) Three-dimensional cyclic voltammograms of PAC (0.25 mmol) in the presence of NO2− (1 mmol) during controlled potential coulometry at 0.45 V versus Ag/AgCl after consumption of (a) 0, (b) 10, (c) 20, (d) 30, (e) 40, and (f) 50 C. Scan rate: 50 mV s−1. (II) Potential−time diagram during constant current electrolysis for the above conditions. Electrode rotation rate: 1000 rpm. Other conditions are the same as for Figure 1.

the cyclic voltammograms of PAC in the presence of nitrite ion during the CPC. The voltammograms show that in parallel to the disappearance of peak A1, the cathodic peak C2 appears. The current of peak A1 (IpA1) becomes about zero with the transfer of about two electrons per molecule of PAC. The electrochemical evidence along with the spectroscopic data of the final product all point to 2-nitroacetaminophen (2NPAC), which would form according to the pathway shown in Scheme 1. The presence of the electron-withdrawing nitro group in the

Figure 3. Cyclic voltammogram of first and second scans of 2NPAC (saturated). In both cases, scan rate 10 mV s−1. Inset: 2NPAC (0.5 mM). Scan rate 100 mV s−1. Other conditions are the same as for Figure 1.

Scheme 1. Proposed Mechanism for Electrochemical Oxidation of PAC in the Presence of Nitrite Ion

Contrary to PAC (Figure 1), at the first cycle, the cyclic voltammogram of 2NPAC shows an irreversible feature with an anodic peak (A3) at 0.69 V vs Ag/AgCl, which belongs to the oxidation of 2NPAC to 2-nitro-N-acetyl-p-benzoquinone-imine (2NPBQ), and the cathodic peak (C2), which corresponds to the reduction of 2NPAC to NHPA (Scheme 1). In the second cycle, the CV showed the new anodic (A4) and cathodic peaks (C4) which correspond to the oxidation of “cathodically generated” NHPA to 2-hydroxylamine-N-acetyl-p-benzoquinone-imine, HAPBQ, and vice versa (Scheme 1).8 The latter peak (C4) is clearer at the upper concentrations of 2NPAC, with lower switching potential and also higher scan rates (Figure 3, inset). In addition, in comparison with PAC, EpA3 is more positive than EpA1. The result was predictable: the attachment of an electron-withdrawing group (EWG) to the phenyl ring increases the oxidation potential. This molecule (2NPAC) has more resistance to oxidation by cytochrome P-450 than PAC. The nitration reaction was also conducted by treating PAC with sodium nitrite according to a procedure described by Chiron and Gomez.4d Contrary to the electrochemical method (yield 85%), both 2NPAC (yield 30%, mp = 158−160 °C) and 3-nitroacetaminophen (3NPAC) (yield 70%, mp = 217−219 °C) were isolated. We think that the regioselectivity observed

structure of 2NPAC causes the oxidation of the 2NPAC to be more difficult than PAC. This feature ensured that the oxidation of 2NPAC did not occur during the electrochemical oxidation of PAC at 0.45 V vs Ag/AgCl. Accordingly, the cathodic peak C2 pertains to the reduction of 2NPAC to N-(4-hydroxy-3-(hydroxyamino)phenyl)acetamide (NHPA) (Scheme 1).6 PBQ is an asymmetric B

DOI: 10.1021/acs.orglett.5b01837 Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 4. Reaction Mechanism for the Synthesis of 2NAPIP

PBQ was found to vary in the order C4 < C2 < C1 < C5. According to these data, C5 and C1 sites are more appropriate sites for the nitration reaction. However, our experimental results confirm that the C2 is the reaction site and 2NPAC was synthesized regioselectively by the anodic nitration of PAC. On the other hand, our computational studies show that the natural charge of the carbons in OBQ was found to vary in the order C6 < C3 < C4 = C5. These data show that C5 and C4 are more positive than other sites. However, our data confirm that the reaction site in electrochemical nitration of OAC is C6 (Scheme 3). The calculated Gibbs free energies of these compounds in the gas phase show that the 2NPAC is 13.9 kcal/mol more stable than that of 3NPAC. The relative stability of 2NPAC is due to the formation of intramolecular hydrogen bonding between the OH and NO2 groups. Our data also show that because of the formation of intramolecular hydrogen bonding between the hydroxyl and nitro groups the 2NOAC is 9.7 kcal/mol more stable than that of 5NOAC. In addition, calculations of the LUMO coefficients of PBQ, OBQ, and APIPox show that the LUMO coefficient of the carbon in the ortho position to the carbonyl carbon is larger than other carbons, which implies that a nucleophilic attack at this carbon should be favored. According to these data, we conclude that the nature of the products that form (2NPAC, 2NOAC, and 2NAPIP) is influenced by the following parameters: (1) natural charge, (2) thermodynamic stability, (3) LUMO coefficient, and (4) electrode surface effects. However, we believe that the orientation of adsorbed PBQ and OBQ on the electrode surface plays an important role in the regioselective synthesis of these compounds and is the reason for the difference between chemical and electrochemical methods. In other words, the latter parameter has a significant effect on the regioselective nitration of PAC and OAC over other parameters such as natural bond orbital. Finally, in this work, electrochemistry was used as a powerful tool for organic synthesis.12 The electrochemical nitration of PAC and OAC has two advantages over conventional methods. First, it is convenient to carry out and uses mild and green conditions with high atom economy (>99%). It proceeds at room temperature and in aqueous solution, without any catalysis, strong acids, or base and cosolvents. Second, in this method, the products were obtained regioselectively in high yields. 2NPAC may lead to minimization of the side effects of acetaminophen and improve the efficacy of the therapy.

Figure 4. Probable orientation of PBQ on the surface of the carbon electrode. The structure of PBQ has been optimized using MM2 calculations.

Electrochemical oxidation of OAC was also studied in the presence of nitrite ion. Since OAC shows the same electrochemical pattern as described for the electrochemical oxidation of PAC in the presence of nitrite ion (evidence a−e discussed previously), the electrochemical behavior of OAC is not reported here. The reaction mechanism for the electrochemical oxidation of OAC in the presence of nitrite ion is presented in Scheme 3. Scheme 3. Reaction Mechanism for the Synthesis of 2NOAC

Since 2NOAC has the same hydrogen-bonding pattern as 2NPAC, the MS spectrum of it showed the same fragmentation pattern observed in 2NPAC and confirmed that the nitro group is positioned ortho to the hydroxyl group. OBQ is an asymmetric molecule which has four different sites leading to four different products (Scheme 3). However, the presence of a triplet (1H) and two doublet of doublet (1H and 1H) peaks in the 1H NMR spectrum of the isolated product does not comply with the structures of 3NOAC and 4NOAC and rejects the synthesis of these compounds during electrochemical oxidation of OAC in the presence of nitrite ion. Nitration of OAC by nitric acid in acetic anhydride was performed by King, who reported a melting point of 279−280 °C for 5NOAC,10 which is much higher than the observed melting point for the electrochemically nitrated OAC (228−230 °C). Therefore, these data confirm regioselective formation of 2NOAC. The electrosynthesis of 2NOAC was performed successfully using both controlled-potential and constant current electrolysis methods. The obtained yields were 68 and 64%, respectively. Electrochemical nitration of APIP was also performed under the same conditions.11 The reaction mechanism for the electrooxidation of APIP in the presence of NO2− is presented in Scheme 4. The yields of 2NAPIP in both controlledpotential and constant current electrolysis methods were 78 and 75%, respectively (for more data, see the Supporting Information). The NBO analysis was used for calculating the partial charge of each atom in the molecules investigated here at BP86/Def2TZVPP level of theory. The natural charge of the carbons in

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b01837. Detailed experimental procedures and characterization data for all compounds; FT-IR, 1H, 13C NMR, and MS spectra of 2NPAC, 2NOAC, 3NPAC, and 2NAPIP; ORTEP view of X-ray crystal structure of 2NPAC; TLC of 2NPAC; calculated charge and LUMO coefficient for C

DOI: 10.1021/acs.orglett.5b01837 Org. Lett. XXXX, XXX, XXX−XXX

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PBQ, OBQ, and APIPox; chemical structures of the possible nitrated compounds (PDF) crystallographic data for 2NPAC (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the Bu-Ali Sina University Research Council and CEDEFMCS for their support of this work. REFERENCES

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DOI: 10.1021/acs.orglett.5b01837 Org. Lett. XXXX, XXX, XXX−XXX